Animal experiments and clinical trials have suggested a beneficial effect of fish oil-derived (n-3) polyunsaturated fatty acid (PUFA) supplementation on atherosclerosis, atherothrombotic disorders, autoimmune and inflammatory diseases. The prevalence of these disorders increases with age and has increased the interest of older adults in the use of fish oil supplements. However, without adequate antioxidant protection the substitution of membrane fatty acids with highly oxidizable (n-3) PUFA of fish oil may potentiate peroxidation of cellular membranes. The immune system declines with age and is susceptible to oxidative stress. Free radical formation and lipid peroxidation (LP) increase with age and contribute to this decline of immune response. We and others, have shown that fish oil suppresses the immune response, particularly in older adults. The mechanism of (n-3) PUFA-induced suppression of immune response has not been elucidated. It is hypothesized that the fish oil-induced decrease in T cell-mediated function is due in part to a relative decrease in vitamin E/PUFA ratios in peripheral blood mononuclear cells (PBMC) with potentiation of free radical formation and peroxidation of cellular membranes and/or production of eicosapentaenoic acid (EPA)-derived prostanoids such prostaglandin (PG0E3. Thus supplementation with vitamin E should prevent the (n-3) PUFA-induced suppression of T cell-mediated function by increasing the vitamin E/PUFA in PBMC membranes, preventing LP in general and/or specifically by decreasing formation of EPA-derived eicosanoids. This hypothesis will be tested by randomly assigned 40 healthy subjects (>65y) to one of 4 groups. Group I will supplement their usual diet with 2.5 g/day of (n-3) PUFA and a placebo capsule (for vitamin E) for 3 mo. Group 2, 3 and 4 will supplement their usual diet with 2.5 g/day of (n-3) PUFA and 100, 200 and 400 UI vitamin E/d, respectively, for 3 mo. Changes in in vivo and in vitro indices of the immune response, PBMC vitamin E/PUFA ratio and their production of PGE2, PGE3, H2O2, and LP will be measured and correlated before and after supplementation. The relative contribution of EPA-derived eicosanoids and free radicals will be further investigated in vitro by using specific cyclooxygenase and lipoxygenase inhibitors and free radical quenchers (catalase and spin trappers). Through these studies we will determine 1) the required intake of vitamin E necessary for optimal immune response and antioxidant protection in older adults consuming (n-3) PUFA, and 2) the mechanism of (n-3) PUFA-induced suppression of T cell-mediated function.